Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancer types which 5-year survival is less than 10%. Gemcitabine (GEM) remains the front-line standard-of-care for PDAC; however, pronounced chemoresistance driven by the dense desmoplastic stroma severely constrains its clinical efficacy. The tumor stroma can comprise more than 90% of the total volume, where fibrosis elevates interstitial pressure, compresses blood vessels, impedes penetration, and promotes hypoxia-driven angiogenesis, ultimately forming a vicious cycle. Thus, it is important to attenuate fibrosis and normalize neovasculature for GEM treatment. We therefore designed acid-responsive "rocket-like" Si-G@Ca-H/uPA that exploit Halofuginone (HF), restoring stroma homeostasis, and urokinase plasminogen inhibitor IPR-803 (uPA), loosening the collagen-rich matrix and inhibiting tumor angiogenesis, in the outer shell, followed by GEM-loading mesoporous silica nanoparticles (MSNs) in the core. In this way, the sequential release of HF and uPA remodeled the stroma, enabling deeper penetration of GEM. In PDAC mouse model, Si-G@Ca-H/uPA group showed significantly marked tumor regression without any side effect, presenting great translational potential.
This prospective, phase III, randomised, multicentre, double-masked study (jRCT2031210122) assessed the intraocular pressure (IOP)-lowering efficacy, tolerability and superiority of netarsudil 0.02% + concomitant latanoprost 0.005% to placebo + latanoprost in Japanese participants with primary open-angle glaucoma (POAG) or ocular hypertension (OHT) who have inadequate IOP reduction with latanoprost monotherapy. Participants received latanoprost once daily for 6 weeks. Eligible participants (n = 246) with POAG (n = 165) or OHT (n = 81) were randomised (1:1) to netarsudil + latanoprost (n = 122) or placebo + latanoprost (n = 124) for 4 weeks. Primary endpoint was mean diurnal (MD) IOP at week 4, with superiority demonstrated if the between-group difference in least squares mean MD IOP was < 0 and p < 0.05. Secondary endpoints included MD IOP at weeks 1 and 2. Adverse events (AEs) were recorded. At week 4, MD IOP (standard error) was 15.29 (0.17) versus 17.65 (0.17) mmHg with netarsudil + latanoprost versus placebo + latanoprost, respectively [difference, - 2.36 (p < 0.0001)]. The differences at weeks 1 and 2 between netarsudil + latanoprost and placebo + latanoprost were - 2.47 and - 2.41 (p < 0.0001), respectively. At each visit, netarsudil + latanoprost significantly reduced MD IOP versus placebo + latanoprost (p < 0.0001). Of those receiving netarsudil + latanoprost, 64.8% reported AEs versus 21.0% receiving placebo + latanoprost. Conjunctival hyperaemia was the most reported AE in both groups (53.3% vs. 6.5%). No serious AEs were reported. Netarsudil + latanoprost was superior to placebo + latanoprost in lowering elevated IOP in Japanese patients with POAG or OHT. No new safety signals were reported. Japan registry of clinical trials: jRCT2031210122. Glaucoma is often caused by an abnormal build-up of fluid in the eye. This raises pressure inside the eye (intraocular pressure), known as ocular hypertension (OHT). OHT can damage the optic nerve to the brain and lead to gradual vision loss. Primary open-angle glaucoma (POAG) occurs when the eye’s drainage channels become blocked. This stops fluid from leaving the eye, raising intraocular pressure. POAG and OHT can be treated with eye drops containing medicine, such as latanoprost or netarsudil, that reduce intraocular pressure. Individually, these medicines may not be enough to lower intraocular pressure to the necessary target; some people may need two or more medicines. This study looked at how well latanoprost and netarsudil work together to lower intraocular pressure in Japanese adults with POAG or OHT and above-normal intraocular pressure. Half of the participants were treated with latanoprost and netarsudil. The other half were treated with latanoprost and eye drops containing no medicine (placebo). After 1, 2 and 4 weeks of treatment, there was a bigger reduction in intraocular pressure with latanoprost and netarsudil than with latanoprost and placebo. Mild side effects occurred in 65% of the latanoprost and netarsudil group and in 21% of the latanoprost and placebo group. Reddening of the eye caused by enlarged blood vessels (known as conjunctival hyperaemia) was the most common side effect. Overall, latanoprost and netarsudil were better than latanoprost and placebo at lowering intraocular pressure. Side effects were more common with latanoprost and netarsudil than with latanoprost and placebo, but none were serious.
Advances in machine learning have transformed structural biology, enabling swift and accurate prediction of protein structure from sequence. However, key challenges persist in modeling side-chain packing, condition-dependent conformational changes and biomolecular interactions, largely because of limited high-quality training data. At the same time, emerging experimental techniques such as cryo-electron microscopy (cryo-EM), cryo-electron tomography (cryo-ET) and high-throughput crystallography are generating vast amounts of structural information but converting these data into mechanistically interpretable atomic models often remains difficult. Here we show that integrating experimental measurements directly into protein structure prediction can overcome these limitations. We introduce ROCKET, an augmentation of AlphaFold2 that refines predicted structures using cryo-EM, cryo-ET and X-ray crystallography data. By optimizing structures in the space of coevolutionary embeddings rather than Cartesian coordinates, ROCKET captures biologically meaningful structural variation that is inaccessible to AlphaFold2 alone and to existing automated modeling approaches, especially when the signal-to-noise ratio is low. ROCKET enables scalable, automated model building without retraining and provides a general framework for integrating experimental observables with biomolecular machine learning.
Wheat is the most important food crop worldwide with second rank next to maize in total production. It's production has to be increased by 70% to feed the rocket shooting wold population by 2050.But the production of wheat was challenged by salinity stress and lead to loss of about 50% products. Improving the germination performance of bread wheat under salinity stress is the basic mechanism to solve the product loss and enhance breeding strategies in wheat. Hence, the present study aimed to identify salt tolerance genes and genomic loci related to germination performance under salinity stress in wheat, providing insights into salinity-responsive pathways and candidate genes to support future breeding strategies for improved salt tolerance at early developmental stages. To obtain this target Genome wide association study was performed on 154 Ethiopian bread wheat genotypes. Three groups of bread wheat were identified under salt stress as tolerant, moderate tolerant and sensitive. Based on this a total of 31 QTNs were revealed through GWAS analysis. Finally 10 functional genes were identified and annotated as functional genes to determine their effects on germination performance traits. Most of the genes were involved in transcription regulation, carbohydrate metabolism, immune response and cell cycle regulation and stress signalling. The germination trait based phenotyping of the genotypes, revealed QTNs and candidate genes, mechanism of action identified during annotation with respect to function increase the understanding for better germination performance of bread wheat under salt stress.
Armed conflict poses unique challenges to maternity care, reshaping both the physical infrastructure and emotional labor of birth. This study examines how midwives in a northern Israeli hospital navigated birth work during sustained rocket threats in 2023-2024. This focused ethnography draws on interviews with five hospital midwives and twelve women from the same region, conducted during the war. Using interpretative phenomenological principles, the analysis highlights the embodied, emotional, and ethical dimensions of midwifery under duress. Three central themes emerged: 1. Midwifery in Displaced Space - Navigating Work and Meaning in a Temporary Birth Unit: Midwives described spatial and emotional dislocation resulting from working in an improvised setting, which challenged their capacity to maintain intimacy, privacy, and professional presence. 2. Crisis Work and Ethical Commitment - Practicing Midwifery under Threat: Despite fear and exhaustion, midwives expressed a strong ethical commitment to providing care and viewed birth work as meaningful resistance during wartime. 3. Ideal vs. Real - Intimacy, Intervention, and the Midwife-Woman Bond: Fewer births allowed more individualized care, yet also led to heightened surveillance and increased interventions. Diverging midwifery philosophies emerged, particularly regarding women's autonomy and institutional constraints. Midwifery during wartime revealed both vulnerability and resilience. While the crisis disrupted standard routines, it also opened possibilities for woman-centered, relational care - alongside new pressures of accountability, ambivalence, and institutional constraint. The study contributes to the anthropology of birth in crisis zones and highlights the ethical complexity of providing care in contexts of both threat and trust.
From oil drums to flying rockets, cylindrical shells are valued for their load-carrying capacity. When sufficiently compressed, they buckle, with the phenomenon taking many forms, from periodic diamond-shaped buckles to localized elephant footing. The precise physical mechanisms of buckling are different, for example, in empty shells and shells with a solid core. However, despite the abundance of liquid-filled shells in industry and everyday life, their buckling is largely overlooked. Here, we compress beverage cans and identify a sequential buckling instability that localizes circumferential rings above a critical level of compression. Combining measurements of the anisotropic material properties of the shell with modelling based on the nonlinear Swift-Hohenberg equations, we demonstrate that fluid-filled shells can support a multiplicity of localized solutions, which are induced by the nonlinear hoop stress of the shell and sequentialize through homoclinic snaking. This establishes a rare link between idealized mathematical studies of pattern formation and physical realizations of spatially-localized buckling phenomena. These findings serve as a blueprint for exploring localized patterns induced by material nonlinearities, near-incompressibility and pressurization in other physical systems.
To address the challenges of data processing caused by uncertain emissivity in multispectral radiation thermometry, this paper proposes a temperature retrieval method based on the Chaotic Artificial Hummingbird Algorithm (CAHA). Without relying on an assumed emissivity model, the method can automatically identify the emissivity distribution and selects the optimal output through multiple iterations to enhance accuracy. Simulations and offline tests conducted on rocket nozzles demonstrate that CAHA maintains high accuracy both in noise-free conditions and under 5% noise, with a single execution time of approximately 0.15 s. Furthermore, the method is validated through experiments on blackbody sources and candle flames: the relative error in retrieved temperature for blackbody sources remains below 0.93%, while the retrieved outer flame temperature of candle flames shows a relative error of 0.66% compared with thermocouple measurements. Combining high precision with rapid computation, this method is suitable for practical applications in radiation thermometry.
Machine learning algorithms have great potential for classifying brain activity, and lightweight classifier algorithms, requiring little computational resources, can be used on low-energy neuromorphic hardware designed for implantable neuroprosthetics. One of these efficient algorithms, the Liquid State Machine, implements the concept of Spiking Neural Networks and has been shown to achieve outstanding results on the task of whisker stimulus detection from the mouse barrel cortex, a widely used model system. While this is promising for neuroprosthetics, it has been unclear how a Spiking Neural Network or other machine learning algorithms perform on data recorded from awake mice and how trained models generalize across individuals, the latter being relevant to transferring trained models to new hardware. Using laminar multi-electrode local field potential recordings obtained from four mice performing a single-whisker detection task, we benchmarked the performance of a collection of lightweight classification algorithms. We found that the Liquid State Machine, a generalized linear model, and the time series classifier ROCKET are the most accurate for stimulus detection. Among those, the Liquid State Machine achieved the fastest model training and inference runtime and provided robust accuracy across individual mice. Additional analyses show that there is no significant improvement in using multiple cortical layers as input for the model and that 40 ms of stimulus recording is sufficient to maintain high detection accuracy.
The treatment of osteoporosis remains a critical challenge due to the limitations of current therapies in simultaneously restoring homeostasis of bone metabolism and modulating the chronic inflammation of bone microenvironment. While the acidic microenvironment greatly exacerbates bone resorption, it also lays the foundation for the application of responsive therapeutic nanoplatforms. Herein, inspired by the rocket-like responsive cascade release principle-defined by a "booster-payload" mechanism, in which a metal ion-doped mesoporous silica shell serves as an early-release booster and a calcium sulfide core acts as a sustained-release payload-a bone-targeted nanoplatform (CSM3P) was developed. This platform integrates calcium sulfide nanoparticles with magnesium/manganese-doped mesoporous silica for bone targeting. It leverages the pathological acidic microenvironment of osteoporosis to enable stimuli-responsive and stepwise release of multiple mineral ions (Mg2+/Mn2+/Ca2+) and hydrogen sulfide (H2S), coordinates bone regeneration and regulation of the osteoimmunological microenvironment and thereby achieves metal-gas targeted therapy for osteoporosis. This acidic responsive and sequential ion/gas release model establishes a self-reinforcing therapeutic cycle, where the pathological acidity itself drives a synergistic and adaptive treatment regimen. Both in vitro and in vivo evaluations demonstrate the superior efficacy of CSM3P in ameliorating the inflammatory bone microenvironment and rebalancing bone remodeling. This work offers a novel paradigm for intelligent, feedback-driven nanotherapy against osteoporosis and other microenvironment-associated diseases.
Castleman disease (CD) is a complex lymphoproliferative disorder characterized by nonspecific clinical manifestations and imaging features. When occurring within the mediastinum, it is easily confused with other diseases, posing diagnostic challenges. We report a case of unicentric hyaline vascular Castleman disease (UCD) located in the posterior mediastinum. This case report is supplemented by a retrospective analysis of the literature, aiming to enhance understanding and improve diagnostic accuracy for this condition. This paper provides a detailed account of the clinical data, imaging findings, diagnostic and therapeutic process of a 28-year-old female patient with a posterior mediastinal UCD. Seven years ago, the patient incidentally found a left posterior mediastinal mass during an outpatient visit for a respiratory tract infection at another hospital. A needle biopsy at that time suggested post-infectious reactive lymphadenopathy. After antimicrobial therapy, respiratory symptoms improved, but intermittent back pain subsequently occurred without prompt attention and follow-up. The patient recently presented for follow-up due to persistent left-sided chest pain unresponsive to analgesics. Imaging examination revealed a significantly enlarged lesion compared to previous findings, now extending to the left thoracic ninth intervertebral foramen region. Additionally, localized increased bone density was observed adjacent to the ninth rib. The patient ultimately underwent complete surgical resection, with postoperative pathology confirming hyaline vascular Castleman disease. No adjuvant radiotherapy or chemotherapy was administered postoperatively. The definitive diagnosis of posterior mediastinal hyaline vascular type CD relies on histopathological examination of surgically resected specimens combined with immunohistochemical staining to establish diagnosis and classification. Imaging features of a hyper-vascular mass in the posterior mediastinum, exhibiting persistent marked enhancement with peri- and intra-tumoral tortuous feeding vessels, may provide valuable diagnostic clues for this disease. Radiologists and relevant clinicians should enhance the recognition of this entity to facilitate the formulation and optimization of diagnostic and therapeutic strategies.
Artificial intelligence (AI) is rife with optimization problems, from automating feature engineering and hyperparameter tuning to training intricate neural networks. Finding a balance between exploration and exploitation remains a significant challenge, despite the widespread usage of metaheuristic algorithms to tackle these complex black-box problems. We suggest the River Erosion and Deposition Algorithm (REDA), a unique search technique for numerical and engineering optimization, as a solution to this problem. In order to simulate a dynamic equilibrium state, the algorithm incorporates an adaptive search weight that alternates cyclically between local exploitation and global exploration. While a randomized Boolean operator preserves population diversity, its position-updating process incorporates a stochastic recombination of current population members with an elite memory set to direct the search. We used 19 constrained engineering optimization problems and 29 unconstrained CEC2017 benchmark test functions in a systematic validation process to assess REDA's performance. According to experimental results, REDA performs noticeably better than 13 cutting-edge comparator algorithms. The higher performance of REDA, especially in low-dimensional areas, is confirmed by statistical analyses based on the Friedman test and the Wilcoxon signed-rank test. Furthermore, when utilized to detect parameters in a solar system, REDA showed good accuracy and stability. Collectively, these tests verify that the proposed method effectively balances exploration and exploitation in difficult solution domains.
Planar honeycomb structures, especially biomimetic hexagonal honeycombs, are widely used in energy-absorbing equipment because of their excellent out-of-plane deformation resistance. However, their significant mechanical anisotropy, manifested by the large discrepancy between out-of-plane and in-plane responses, greatly restricts their broader applications. Inspired by spiral-reinforced thin-walled biological tubular systems, such as animal tracheae and plant vessels, this study proposes a biomimetic reinforcement strategy by embedding spiral structures along the thin walls of planar honeycombs. To validate the feasibility of the proposed design, biomimetic honeycomb specimens were fabricated using 3D-printing technology and tested under compression along different loading directions. Furthermore, a numerical model validated against the experiments was developed to reveal the underlying enhancement mechanism. The results demonstrate that the proposed biomimetic honeycomb preserves the favorable out-of-plane performance of the conventional hexagonal honeycomb, while improving the in-plane energy absorption capacity by up to 70%. The biomimetic spiral reinforcements enable more effective load transfer under multidirectional loading, resulting in a more uniform plastic stress distribution over the entire structure and activating a larger deformation region for energy dissipation. The present work provides a bioinspired strategy for developing lightweight energy-absorbing structures for potential applications in aerospace, rail vehicles, marine engineering, and civil structures.
Local radiation injury-induced frailty seriously impacts the quality of life of patients undergoing radiotherapy or nuclear accident casualties and causes a significant medical and economic burden. However, the underlying mechanisms of the frailty remain unknown. In this study, a unique population of hyperactive GAL-9high neutrophils is identified with characteristics of elevated ROS, NETs, and IFN-γ, prolonged lifespan, etc. These neutrophils infiltrate into multiple organs to induce injuries, also disrupt the bone marrow microenvironment, drive sustained bone marrow myeloid-biased differentiation, and resist clearance by bone marrow macrophages, serving as a crucial factor to exacerbate frailty. GAL-9 protein is demonstrated to play a vital role in the regulation of neutrophil hyperactivity. EccDNA shedding after skin radiation injury is shown to activate the JAK1/2-STAT1 pathway in splenic GMP cells, which is a potential origin of GAL-9high neutrophils. In summary, our results highlight the significance of the previously unrecognized hyperactive GAL-9high neutrophils to exacerbate frailty through a 'skin-spleen-bone marrow-multiple organs' axis after local radiation injury.
To explore the imaging effect of the novel tracer, mitoxantrone hydrochloride injection for tracing (MHI), on cervical lymph nodes during thyroid cancer radical surgery, and its clinical value in assisting the identification of parathyroid glands and recurrent laryngeal nerves. A prospective randomized controlled study was conducted from January 2022 to March 2025, recruiting 220 thyroid cancer cases at Tianjin First Central Hospital. The CONSORT checklist was followed. Among the participants, 64 were male and 156 were female, with ages ranging from 26 to 69 years. Based on different lymph node tracing methods, the cases were divided into three groups: the MHI lymph node tracing group (MHI group, n = 100), the nanoparticle carbon lymph node tracing group (nanoparticle carbon group, n = 60), and the no lymph node tracer group (control group, n = 60). All patients underwent total thyroidectomy and regional lymph node dissection. General clinical indicators were recorded, and the number of detected lymph nodes, positive metastasis, surgical field clarity, parathyroid gland identification rate, and error excision rate were compared. Serum calcium, parathyroid hormone (PTH) levels, and complications were analyzed at different time points. Statistical analysis was conducted using one-way ANOVA, chi-square test, and two independent sample non-parametric tests. The MHI group and nanoparticle carbon group had significantly shorter operative times, less cervical drainage volume, and shorter hospital stays compared to the control group (P<0.05 for all). The MHI group had significantly higher staining scores, successful tracing rates, and surgical field clarity scores compared to the nanoparticle carbon group (P<0.05 for all). The MHI group had significantly more lymph nodes removed, a higher number of positive metastases, and a higher parathyroid identification rate compared to both the nanoparticle carbon and control groups. The error excision rate for the parathyroid gland in the MHI and nanoparticle carbon groups was significantly lower than in the control group (P<0.05 for all). On post-operative days 1 and 5, the MHI group had significantly higher serum calcium and PTH levels compared to both the nanoparticle carbon and control groups. However, on post-operative day 1, there was no difference in serum calcium levels between the nanoparticle carbon and control groups (P>0.05), but the PTH level in the nanoparticle carbon group was higher than that in the control group. On post-operative day 5, the nanoparticle carbon group had higher levels of both serum calcium and PTH compared to the control group (P<0.05 for all). On post-operative days 14 and 30, there was no significant difference in serum calcium and PTH levels between the MHI and nanoparticle carbon groups (P>0.05). The MHI and nanoparticle carbon groups had a lower risk of facial numbness, hand and foot convulsions, and dysphagia compared to the control group (P<0.05 for all). MHI can provide several advantages during radical thyroid cancer surgery, including clear lymph node tracing within the surgical field, enhanced nodal identification and pathological retrieval, and improved surgical visibility and nodal harvest. These advantages can contribute to reduce the risk of injury to the recurrent laryngeal nerve and parathyroid glands.
Quantum chemical mapping of weak interaction networks in N2O4/HNO3/H2O and HNO3/N2O4 propellant systems is reported. Electrostatic potential analysis identifies HNO3 as the dominant hydrogen bond donor (+64.28 kcal/mol), forming the strongest complex with H2O (-9.45 kcal/mol). In the ternary HNO3···N2O4···H2O cluster, water acts as a polarization catalyst, inducing a cooperative stabilization of 1.99 kcal/mol by enhancing the HNO3 donor ability. Most significantly, in water-depleted 2HNO3···N2O4 clusters, a specific weak interaction topology prefigures a concerted double proton transfer pathway (ΔE‡ = +32.1 kcal/mol), forming [HNO2···NO2+]···NO3- ion pairs. This finding provides a new theoretical hypothesis for the source of ions beyond the dissociation of HNO3 in future studies of corrosion origin. Solvation models further confirm the persistence of these weak interaction networks and the feasibility of the proposed proton transfer pathway in the liquid N2O4 environment.
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive disorder caused by destabilization of serum transthyretin (sTTR). Acoramidis, an approved therapy that achieves near-complete (≥90%) sTTR stabilization, demonstrated clinical benefit through month 30 in ATTRibute-CM, which was incremental through month 42 in the open-label extension (OLE); however, the longer-term durability of outcomes has not been reported. To evaluate the long-term efficacy and safety of acoramidis through month 54. This OLE of the ATTRibute-CM randomized clinical trial is an international, multicenter, ongoing OLE study. Data accumulated between October 2021 and April 2025 through month 24 of the OLE (month 54) are reported. Participants (aged 18-90 years) who completed ATTRibute-CM and met the OLE eligibility criteria were invited to enroll in the OLE. Data were analyzed from May 2025 through November 2025. All OLE participants received open-label oral acoramidis, 800 mg, twice daily. Acoramidis recipients from ATTRibute-CM continued therapy (continuous acoramidis) and placebo recipients switched to acoramidis (placebo to acoramidis). The primary outcome was time to event for all-cause mortality (ACM), cardiovascular-related mortality (CVM), and first cardiovascular hospitalization (CVH), which was assessed for both groups. Biomarkers of disease progression (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), sTTR, functional capacity (6-minute walk distance [6MWD]), and heart failure-related health status (Kansas City Cardiomyopathy Questionnaire-Overall Summary [KCCQ-OS] score) were analyzed. In ATTRibute-CM, 632 participants were randomized to receive acoramidis (n = 421) or placebo (n = 211); mean (SD) age was 77.3 (6.6) years, and 62 participants (9.8%) were female. Overall, 389 participants enrolled in the OLE (263 in the continuous acoramidis group; 126 in the placebo-to-acoramidis group). Continuous acoramidis treatment reduced risks of ACM (hazard ratio [HR], 0.55; 95% CI, 0.42-0.74; P < .001) and CVM (HR, 0.51; 95% CI, 0.36-0.71; P < .001) through month 54, with consistent efficacy across all prespecified subgroups. Continuous acoramidis reduced time to first CVH (HR, 0.53; 95% CI, 0.42-0.69; P < .001) through month 54. Through month 54, continuous acoramidis stabilized increases in NT-proBNP, sustained higher sTTR levels, and stabilized KCCQ-OS score and 6MWD. Switching from placebo to acoramidis at month 30 was associated with stabilization of NT-proBNP and KCCQ-OS score and improvements in sTTR and 6MWD through month 54. No new long-term safety concerns were identified. In this OLE of the ATTRibute-CM randomized clinical trial, early and continuous acoramidis treatment resulted in sustained incremental reductions in ACM, CVM, and first CVH through month 54. These findings support the importance of early and continuous long-term treatment with acoramidis in ATTR-CM. ClinicalTrials.gov Identifier: NCT04988386.
Sleep disturbances have been associated with Alzheimer's disease (AD), but their relevance in preclinical stages, such as subjective cognitive decline (SCD), and their relationship with brain pathology remain unclear. We used a portable sleep-monitoring headband over four consecutive nights to assess sleep in 19 cognitively unimpaired (CU), 15 SCD, and 20 mild cognitive impairment (MCI) participants with available amyloid positron emission tomography (PET). Linear-mixed-effects models compared sleep parameters across groups, accounting for amyloid burden, age, sex, education, and recording. Regional and voxel-wise analyses examined regional associations between sleep parameters and amyloid burden. MCI patients presented reduced N3 (i.e., deep sleep), while SCD individuals showed longer N1 (i.e., light sleep) duration compared to CU. Regional amyloid burden was associated with longer light and deep sleep in amyloid-positive individuals. Higher education was linked to better sleep efficiency. Sleep changes may serve as early indicators of cognitive dysfunction and regional amyloid accumulation.
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Patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) or preserved EF (HFpEF) show substantial heterogeneity in prognosis. To evaluate the performance of biomarker-driven prognostic models derived from the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved) Trial in the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) and to examine whether baseline risk modified the therapeutic effect of finerenone. This is a prespecified secondary analysis of the FINEARTS-HF trial, which was conducted across 653 sites in 37 countries among adults aged 40 years and older with symptomatic HF and left ventricular EF (LVEF) of 40% or greater. Patients were randomized between September 2020 and January 2023, and data analysis for this study was conducted from September to October 2025. The median (IQR) follow-up period was 32 (23-37) months. Finerenone (titrated to 20 mg or 40 mg) or placebo. EMPEROR-Preserved risk scores for the outcomes of first HF hospitalization or cardiovascular death, cardiovascular death, and all-cause death were calculated in FINEARTS-HF using models incorporating N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, New York Heart Association functional class, history of chronic obstructive pulmonary disease and diabetes, insulin use, and-depending on outcome-age, hemoglobin and albumin levels, HF duration, time from prior HF hospitalization, and sodium-glucose transporter 2 inhibitor use. Estimated risks were compared with observed event rates, and model performance was assessed using Harrell C statistic. Treatment effects were evaluated across risk quintiles (Q1 to Q5) and across the continuous risk distribution. Among 6001 patients (mean [SD] age, 72.0 [9.6] years; 2732 [45.5%] women; 3003 randomized to finerenone and 2998 randomized to placebo), the EMPEROR-Preserved risk model estimated risk of outcomes, with Q5 vs Q1 hazard ratios (HRs) of 10.49 (95% CI, 8.14-13.52) for the composite of HF hospitalization or cardiovascular death and 13.47 (95% CI, 8.79-20.64) for cardiovascular death. The model demonstrated good discrimination. The treatment effect of finerenone was consistent across risk quintiles for first HF hospitalization or cardiovascular death (Q1: HR, 0.93 [95% CI, 0.58-1.49]; Q2: HR, 1.04 [95% CI, 0.76-1.43]; Q3: HR, 0.82 [95% CI, 0.62-1.07]; Q4: HR, 0.81 [95% CI, 0.65-1.01]; and Q5: HR, 0.88 [95% CI, 0.74-1.05]; P for interaction = .68) and remained uniform across the continuous risk spectrum. The EMPEROR-Preserved risk models demonstrated good performance in FINEARTS-HF. Baseline risk did not modify the relative treatment effect of finerenone. ClinicalTrials.gov Identifier: NCT04435626.
Not available.